LPS is the major antigen of gram-negative bacteria. This material is a glycophospholipid consisting of an antigenic, variable size, carbohydrate chain covalently linked to lipid A, the conserved hydrophobic region structurally defined as N,O-acyl beta-1,6-D-glucosamine 1,4′-bisphosphate. Toxicity of LPS is expressed by lipid A through the interaction with B-cells and macrophages of the mammalian immune system, a process leading to the secretion of proinflammatory cytokines, mainly TNF, which may have fatal consequences for the host. Lipid A also activates human T-lymphocytes (Th-1) “in vitro” as well as murine CD4+ and CD8+ T-cell “in vivo”, a property which allows the host's immune system to mount a specific, anamnestic IgG antibody response to the variable-size carbohydrate chain of LPS. On these bases, LPS has been recently recognized as a T-cell dependent antigen “in vivo”.
In order to fully express toxicity, LPS must retain its supramolecular architecture, through the association of several units of glycophospholipid monomers forming the lipid A structure. This conformational rearrangement of the molecule is also fundamental for full expression of the immunogenic characteristic. Therefore, dissociation of these intrinsic properties of the molecule appear to be of crucial interest for proposing the design of LPS-based vaccines related to the prophylaxis of acute and chronic pathologies due to gram-negative bacterial infections like meningococcal meningitis, typhoid fever and Helicobacter pylori-induced gastritis.
Sepsis and septic shock are well defined clinical conditions that are caused by bacteria and by LPS which is the endotoxin elaborated by the bacteria responsible for the above mentioned pathologies. The present inventor has described treatment regimens for septic shock which are based on the use of a defined class of peptides that have been demonstrated to be capable of neutralizing LPS in vivo and protecting mammal from septic shock induced by LPS.
The treatment of a subject for septic shock requires that the subject who has symptoms of LPS toxicity be given the peptide when symptoms appear. The peptide is not an immunogenic compound for the production of antibodies to LPS and it use prophylactically will not prevent sepsis which is caused by the bacteria which release LPS. LPS has immunogenic properties but it is too toxic to be used to induce the production of antibodies in a host who is to be protected from the effects of a bacterial infection and from the effects of LPS which is released by certain bacterial infections.
Certain of the peptides are disclosed in U.S. Pat. No. 5,371,186, and information about the basis of the vaccine is disclosed in J. Endotoxin Res. (1997) 4(4)261-272, which is incorporated by reference.